Currently the prophylactic management of hemophilia A and B patients is replacement of either FVIII or FIX (recombinant or plasma-derived products). These treatments are administered two or three times per week, placing a heavy burden on patients to comply with their prophylactic regime. Despite rigorous management and strict adherence, patients typically experience occasional breakthrough bleeds and require on-demand treatments. If not managed properly, frequent and severe bleeding leads to significant morbidities, especially hemarthropathy. Despite the proven efficacy of the existing agents used to treat hemophilia A and B patients, most adolescents, teenagers and older adults decide to lessen the burden of prophylaxis by reducing the number of injections taken on a routine basis. This approach further compromises the protection needed to adequately manage bleeds.
Consequently, an agent that significantly provides protection and requires relatively infrequent administration is most desired. The optimal therapy should provide protection via weekly or less frequent dosing. Given the current competitive environment, once a week therapies administered intravenously (i.v.) or subcutaneously (s.c.) may be a reality over the next 3-4 years. Therefore, an agent that is administered i.v. or s.c. should provide a superior administration profile with commensurate protection. In the event subcutaneous administration can be achieved, once a week dosing could also offer a significant value to the future treatment landscape due to the reduced invasiveness of this approach.
Another major issue for current hemophilia therapy is the development of inhibitory antibodies against Factor VIII or Factor IX. Approximately 25% of FVIII treated patients generate inhibitors, or neutralizing antibodies against FVIII. Inhibitors are also found in FIX treated patients, although less frequently. The development of inhibitors significantly reduces the effectiveness of replacement therapy and provides a challenge for managing bleeds in hemophilia patients. The current treatment for bleeds in patients with inhibitors to FVIII or FIX is bypass therapy with recombinant Factor VIIa or plasma derived FEIBA. The half-life of rFVIIa is quite short (−2 hours) and thus prophylactic treatment in these patients is uncommon [Blanchette, Haemophilia 16 (supplement 3): 46-51, 2010].
To address these unmet medical needs, antibodies against Tissue Factor Pathway Inhibitor (TFPI) as long-acting agents have been developed. See WO 2010/017196; WO 2011/109452; WO 2012/135671. TFPI is the major inhibitor of the tissue factor initiated coagulation pathway, which is intact in Persons with Hemophilia (PWH), and thus inhibition of TFPI may restore hemostasis in PWH exhibiting inhibitory antibodies to FVIII or FIX. In addition to allowing access to this target, monoclonal antibody (mAb) therapeutics have been shown to have significantly longer circulating half-lives (up to 3 weeks) than recombinant replacement factors. Antibodies that inhibit TFPI also have significant bioavailability following subcutaneous injection. Thus, anti-TFPI monoclonal antibody therapy would meet an important unmet medical need for subcutaneous, long acting hemostatic protection for PWH and PWH with inhibitors.
However, while inhibition of TFPI has been shown to promote coagulation in hemophilic plasmas and hemophilic animals, antibodies against TFPI have relatively short, non-linear half-lives due to a phenomenon known as target mediated drug disposition (TMDD) a process by which the antibody is removed from circulation due to its interaction with a rapidly cleared target or by being sequestered from the plasma due to its co-localization with its target, of the antibody:antigen complex. Therefore, antibodies that avoid TFPI mediated TMDD and have a prolonged half-life would lead to less frequent dosing and reduce the amount of material needed per dose. Furthermore, the need for a lower dose may also make feasible subcutaneous dosing where the dosing volume becomes a limiting step. For example, an optimized anti-TFPI antibody 2A8-g200 (WO 2011/109452), has a half-life of 28 hours when dosed at 5 mg/kg and 67 hrs when dosed at 20 mg/kg in non-human primates.
This relatively short half-life, and the need for larger doses to overcome TMDD, increases the injection burden on patients, limits formulation for subcutaneous dosing and increases the costs of goods. Pharmocokinetic analysis of these antibodies in non-human primates demonstrates that the circulating half-life is not linear with dose, and, particularly at lower doses, is shorter than is characteristic of antibody drugs. A similar pharmacokinetic profile was described in US2011/0318356 A1 for another anti-TFPI antibody. This differential, with a marked shortening of T½ at lower doses, is characteristic of TMDD, where the slower clearance at higher doses is due to saturation of the target.
Accordingly, an unmet medical need exists for better prophylactic treatment for moderate-to-severe hemophilia A and B, especially for those patients with inhibitors against FVIII or FIX. This need would be met by an anti-TFPI antibody having improved characteristics that may be administered intravenously or subcutaneously, and at a reduced frequency, preferably once weekly or less.